ABSTRACT. Soluble oligomers of beta amyloid (A?) protein are the most potent neuroactive structural form of this protein and evidence suggests they cause the synaptotoxic changes resulting in cognitive decline in Alzheimer?s disease (AD) (Selkoe and Hardy 2016, Viola and Klein 2015). A safe and effective drug against A? oligomers should prevent and reverse this synaptotoxicity. CT1812 is the first drug that selectively displaces oligomers from synaptic receptor sites and clears oligomers from the brain into the cerebrospinal fluid (CSF). These first-in-class drugs work by displacing A? oligomers bound to neuronal receptors at synapses. They accomplish this by allosterically modulating a key protein regulator of oligomer receptors (the sigma- 2/PGRMC1 protein complex), thus destabilizing the oligomer binding site and increasing the off-rate of oligomers, which are then cleared into the CSF. As a result, CT1812 restores synapse number and cognitive performance to normal in preclinical AD mouse models (Izzo et al., 2014a, b). This clinical trial project proposes to evaluate the safety and efficacy of three doses of CT1812 on cognitive function in a Phase II randomized, double-blind, placebo-controlled parallel group clinical trial in mild to moderate AD patients. This trial proposes to test CT1812 administered once daily to patients for 6 months, and is designed to measure the short-term cognitive improvement arising from rapid disinhibition of synapses. Since therapeutics directed against A? oligomers should prevent and reverse synaptotoxicity associated with disease and be effective throughout the clinical course of the illness, this drug is being tested in patients with mild to moderate Alzheimer?s disease. This trial will directly test the A? oligomer hypothesis of AD and the effectiveness of CT1812 to improve symptoms of cognitive decline in Alzheimer?s patients. We propose to conduct a trial in 160 A?-positive mild to moderate Alzheimer?s patients (MMSE 18-26) receiving one of three doses of CT1812 or placebo once daily for 6 months, with cognitive testing (ADAS- Cog14, ADCS-ADL, CDR-SB) at baseline, 3 and 6 months. Our primary aim will be to evaluate the safety and efficacy of CT1812 to improve cognitive function. Our secondary aim is to evaluate the effect of CT1812 on changes in serum and CSF protein biomarkers associated with Alzheimer?s disease and synaptic damage (including neurogranin and SNAP25). We hypothesize that rapid increases in synaptic function will correlate with symptom improvement detectable in individual patients within the duration of this proof of concept trial. Completion of this study in AD patients will inform the design and methods of the subsequent long term disease modification Phase III trials with CT1812. Advancement of CT1812 clinical development would substantially improve the lives of the 36 million people worldwide suffering from AD and MCI due to AD, for whom no disease-modifying pharmacological treatments exist.